Predictive biomarkers for endocrine therapy: retrospective study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial

Roseweir, A. K. et al. (2018) Predictive biomarkers for endocrine therapy: retrospective study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. Journal of the National Cancer Institute, 110(6), pp. 616-627. (doi: 10.1093/jnci/djx255) (PMID:29917140)

Abstract

Background: Aromatase inhibitors improve disease-free survival compared with tamoxifen in postmenopausal women with hormone receptor–positive breast cancer. The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial compared exemestane monotherapy with sequential therapy of tamoxifen followed by exemestane. The trial failed to show a statistically significant difference between treatment arms. A robust translational program was established to investigate predictive biomarkers. Methods: A tissue microarray was retrospectively constructed using a subset of patient tissues (n = 4631) from the TEAM trial (n = 9766). Immunohistochemistry was performed for biomarkers, classed into three groups: MAPK pathway, NF-kappa B pathway, and estrogen receptor (ER) phosphorylation. Expression was analyzed for association with relapse-free survival (RFS) at 2.5 and 10 years and treatment regimen using Kaplan-Meier curves and log-rank analysis. All statistical tests were two-sided. Results: In univariate analysis, ER167 (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.59 to 0.85, P < .001), IKKα (HR = 0.74, 95% CI = 0.60 to 0.92, P = .005), Raf-1338 (HR = 0.64, 95% CI = 0.52 to 0.80, P < .001), and p44/42 MAPK202/204 (HR = 0.77, 95% CI = 0.64 to 0.92, P = .004) were statistically significantly associated with improved RFS at 10 years in patients receiving sequential therapy. Associations were strengthened when IKKα, Raf-1338, and ER167 were combined into a cumulative prognostic score (HR = 0.64, 95% CI = 0.52 to 0.77, P <.001). Patients with an all negative IKKα, Raf-1338, and ER167 score favored exemestane monotherapy (odds ratio = 0.56, 95% CI = 0.35 to 0.90). In multivariable analysis, the IKKα, Raf-1338, and ER167 score (P = .001) was an independent prognostic factor for RFS at 10 years in patients receiving sequential therapy. Conclusions: The IKKα, Raf-1338, and ER167 score is an independent predictive biomarker for lower recurrence on sequential therapy. Negative expression may further offer predictive value for exemestane monotherapy.

• Item Type: Articles
• Additional Information: This work was supported by Ontario Institute of Cancer Research, Western Infirmary Breast Cancer Research Fund and European Association of Cancer Research.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mallon, Dr Elizabeth and Horgan, Professor Paul and Dickson, Ms Ashley and Bennett, Miss Lindsay and Roseweir, Dr Antonia and Edwards, Professor Joanne and McMillan, Professor Donald
• Authors: Roseweir, A. K., Bennett, L., Dickson, A., Cheng, K., Quintayo, M.-A., Bayani, J., McMillan, D. C., Horgan, P. G., van de Velde, C. J.H., Seynaeve, C., Hasenburg, A., Kieback, D. G., Markopoulos, C., Dirix, L. Y., Rea, D. W., Mallon, E. A., Bartlett, J. M.S., and Edwards, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Journal of the National Cancer Institute
• Publisher: Oxford University Press
• ISSN: 0027-8874
• ISSN (Online): 1460-2105
• Published Online: 27 December 2017
• Copyright Holders: Copyright © 2017 Oxford University Press
• First Published: First published in Journal of the National Cancer Institute 2017
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher